Metallation of cyano acetic acid compounds



Patented Apr. 27, 1948 cYANo ACETIC ACID MPOUNDS Vernon H. Wallingford, Ferguson, and August H.

Homeyer, Webster Groves, Mo., assignors to Mallinckrodt Chemical Works, St. Louis, Mo.. a corporation of Missouri No Drawing. Application October 29, 1945,

Serial No. 625,450

METALLATION F 1 I This invention relates to the metallation of organic compounds, and with regard to certain more specific features to the replacement of active carbon-bonded. hydrogen atoms of a-cyano esters with metals of the class of the alkali metals and magnesium.

Among the several objects of the invention ma be noted the provision of a general process for bringing about a metallation of the type indicated which is characterized in its high yields, its inexpensive and readily procurable reaction materials, and the facility with which it may be carried out. Other objects will be in part obvious and in part pointed out hereinafter.

The invention accordingly comprises the steps and sequence of steps, and features of synthesis, analysis, or metathesis, which will be exemplified in the processes hereinafter described, and the scope of the application of which will be indicated in the following claims.

Metal organic compounds of the alkali metals and magnesium are exceedingly useful intermediates for the preparation of a wide variety of organic compounds. Many processes have been devised for the preparation of such compounds, but these prior processes have usually offered one or another disadvantage, such as low yields, expensive or unavailable reaction materials, dinicult reaction conditions, and the like. The present invention provides a metallation process which, so far as we can determine, is free of all such disadvantages and which consequently is a highly advantageous procedure to use to achieve the desired results,

It is difiicult to define with accuracy the broad class of materials to which the process of the present invention applies. In general, it appears that the process can be satisfactorily used in all instances where metallation of the type indicated is wanted. Most of such instances seem to com-. prehend the replacement of an active carbonbonded hydrogen on the organic compound with the metal, and the invention will be so described, although it is not intended thereby to so limit the scope of the invention.

From the practical standpoint, metallation of the type herein concerned is usually the formation of the sodium (sodio-) compound. But it will likewise be clearly understood that metallation with the other alkali metals, that is, with lithium, potassium, rubidium, cesium or with magnesium, is not only feasible but also expeditious according to the present invention.

Broadly speaking the process of the present 9 clams. (01. 260-464) be metallated with a metal I diuin, potassium, rubidium, cesium or magnesium.

alcoholate, preferably alcohol-free, in a reaction medium comprising a dialkyl carbonate. This may be represented by thefollowing equation: l I I m'aooo n-onwm-oolx MOR v where R is hydrogen or an aromaticor saturated aliphatic hydrocarbonradical, M is lithium, so-

R' is the radical of. the alcoholate, and It! and Xare alkyls. a I

Whether or not the dialkyl carbonate actually enters into the reaction has not yot been definitely established. Its presence appears to be an important factor. I r

The reaction may be forced to substantial completion by heating, as it progresses, to distill off the product alcohol (R'OH inQthe above equation). In case the original metal alcoholate contains alcohol, such alcohol is likewise removed by this distillation procedure, This procedure, while somewhat optional, is highly advantageous in its improvement of the yield of metallo-jcompound obtained. a

The following examples illustrate the present invention. They are exemplary, only.

EXAMPLE 1 Ethyl s-cyano-p-methylphetzylacetate Sodium ethylate, substantially free of alcohol, was prepared by dissolving sodium metal (3.74g.) in anhydrous ethyl alcohol ('75 ml.) in a threethe sodium had dissolved thecondenser was arranged for distillation and the excess alcohol was distilled ofi and the residue was heated at reduced pressure until the sodium ethylate was substantially free of alcohol. After cooling the solid cake of sodium ethylate was broken up. Diethyl tion flask to a small packed column, the metallation reaction was brought to completion by heating the. reactantsat -100 0. until no more alcohol was obtained as distillate at the head of the column under mm. pressure.

The presence of a high yield of metallated ethyl c-cyano-p-methylphenylacetate was shown by alkylating with an excess of ethyl bromide. A good yield of ethyl a-cyano-a-ethyl-p-methylinvention comprises treating c-cyano esters to 55 phenylacetate, having a boiling point of 104-108 3 C. at about 2.5-

and a refractive index of about n 1.4985 was obtained.

EXAMPLE 2 ,n-Propyl a-cyanoz'socaproate Sodium propylate, substantially free of alcohol,

was prepared by the method described in Ex-w ample 1 for the preparation of sodiumethylate, by dissolving sodium (5.0 g.) in anhydrous ne propyl alcohol (100 ml.) and then removing the excess alcohol under vacuum. Dienepropylcan I bonate (80 ml.) and n-propyl a-cyanoisocaproate (39.5 g.) were added and the resulting-mixture:

stirred until all of the sodium propylate was dissolved. After connecting the small reactioniiiaslg to a small column, the metallation reaction=wasbrought to completion by heating the reactants at 90-100 C. until nor more n-propyl alcoholwas obtained as distillate at the head of the column under 150mmpr ssurei he pr sence o a hieh ry eld oftallated n prom-1: aecyanoisocaproate waszshownby v ing with an excess of-zethyl -bromide: A high yield of n-propyl a-cyano-a-ethylisocaproate was obtained. The boiling point of the ester was 655-459 C. at 0.4 to 1059mm. pressure. The index of refraction of the ester was about n 1.4.299.

Carrying outthe above metallation procedures without the simultaneous removal, by distillation; of-the alcohol -produced in: the reaction, is entire ly ieasible; butathe yield is decreased: from that otherwise obtainable.

Attention is directed to our copending-Patent 2,891,530; which is a 'continuation in-part of and was cope'ndingwith our Patent 2; 35 l; 85.

In view of the above, it wil-lbe-seen-that the several objects of the invention are "achieved-and other advantageous results attained;

As many-"changes could 'be madein-theaabove:

processes-"without 'departing- 'fiiom the scope of. the invention, it is intendedthat -all matter contained" inthe above-description I shall -be *intere preted' as illustrative and not ima limiting sense.-

We claim: r

1 The method of metallating and-eyano: ester.

of thefollowing structure R-CH(CN) 'COX where R is selected from the -group consisting of hydrogen aromatic hydrocarbon. radicals,- and saturated aliphatic hydrocarbon: radicals, and ,X

is an :allgylradical, which comprises reacting the. esterwith an anhydrous alcoholatetof .ametal. se-- lected from the v group consistingbf -sodium,.po-

tassium and, magnesium in. a reaction .medium.

consisting. essentially of: a .dialkyl carbonate.

:2; The method of metallating an..a-cyano.ester- (lithe-following:structure: I

R' CHiCN)" 602K.

where.R,is selected -from-the group .consisting of hydrogen, aromatic hydrocarbon radicals, and) saturated. aliphatic hydrocarbon radicals, and X' is .analkyl radical, which comprises reactingtli'fl. ester. with .an anhydrous alcoh'olate of a metal I selected Qirom .the group consisting of sodium. po-

tassium (and 1 magnesium in a reaction. medium consistingessentiallyjof a dialkyl jcar-bonate, and

removing alcohol.

3. The method ofmetallating an u-cyano ester of the following structure:

R-C'I-HCN) -CO2X where R is selected from the group consisting of hydrogen, aromatic hydrocarbon radicals, and

saturated aliphatic hydrocarbon radicals, and X is an alkyl radical, which comprises reacting the ester withananhydrous al-coholate of a metal selected from the group consisting of sodium, potassium. and magnesium in a reaction medium consisting essentially of a dialkyl carbonate, subjecting the mixture-to distillation for removing alcohol thereirom.

4. The method of metallating ethyl u-cyanop-methylphenylactate, which comprises reacting the ester with anhydrous sodium ethylate in a reaction. medium consisting essentially of diethyl carbonate.

5. The method of metallating n-propyl a-cyan-oisocaproate, which comprises reacting the ester with anhydrous sodium prepylate 1 1173, reactlon medium consisting-essentiallyof di n-propyl car bonate:

6; The method of metallating ethyl a-cya-no p-methylphenylacetate, which comprises-mixingand -heati-ng the ester with anhydrous alcoholree sodium ethylate in a reaction-mediuJn-consisting essentially-of diethyl carbonate, natomtinuous1y-subjectingthe mixture to distillationfor removing alcohol.

'7. The method of metallatingn-propyl a-cydium'; potassium and magnesium ina reactio'n bonat-e; r

9: The method oi met'allati-ng;n-prdpyl ix-c-yano -isocaproate, which comprises ractingjtheester with am anhydrous alcoholate-ofa me'talselectedfrom the group consisting-of soditirnfpo medium consisting; essentially ofa dialkylcartassium and magnesium ina reactio mediumconsisting essentially of a di'alkyl= carbonate.

VERNON WALLINGFQRD AUGUST HHOMEYE-R:

REFERENCES .CITED Th -followine refe ce file. f. this. p tent:

UNITED STATESIPATENTS;

Name

are of record in the Number 7 Date I 236K003 n ER REFER NCES- Lux., Ber. Ider Deut; Chem: Gesellfl vol; 62"

(1929) pages 1824-1827.

Conradet-al-. A-nnalin derGhem; (Tubig) vol. 20441880); pages-121;-129; ;-13l

Jones 21,194 

